Chronic type B hepatitis is a serious infectious disease caused by hepatitis B virus (HBV) and prevalent throughout the world, and is closely relevant to the occurrence of hepatic cirrhosis and liver cancer. China is a high-risk area of HB. The results of seroepidemiological survey of viral hepatitis in China from 1992 to 1995 indicated that the persons carrying the surface antigen (HBsAg) of hepatitis B virus in China accounted for 9.7% of the population, and it was estimated that about 130 millions persons were HBV carriers. A study on the epidemiological situation of viral hepatitis in China demonstrated that the annual reported incidence of HB was increased from 21.9/100 thousands in 1990 to 53.3/100 thousands in 2003, showing an obvious ascending tendency (Wang Xiaojun, Zhang Rongzhen, Hu Yuansheng, et al, Monitoring of Diseases, 2004, 19(8): 290-292). Chronic HB not only seriously affects human health, but also imposes heavy economic burden on a family and society. Therefore, Chronic HB has become one of significant public health concerns in China.
The drugs useful for treating chronic HB mainly include two types—immunomodulator and nucleoside inhibitor of DNA polymerase (Loomba R., Liang T. J., Antivir. Ther., 2006, 11(1): 1-15). The former includes: interferon-α2b (IFN-α2b, Intron A®) and PEGylated interferon-α2a (peg-IFN-α2a, Pegasys®); the latter includes: Lamivudine (Epivir-HBV®), Adefovir Dipivoxil (Hepsera®) and Entecavir (Baraclude®). Comparatively, the number and type of drugs available for treating HB in clinic are still limited. Thus, it is extremely important to continuously research and develop new safe and effective anti-virus drugs, in particular those having a completely new mechanism of action.
Deres et al. reported heteroaromatic ring substituted dihydropyrimidine (HAP) compounds represented by Bay41-4109 and Bay39-5493, which compounds could act to suppress the replication of HBV by preventing the normal formation of nucleocapsid. The preclinical data demonstrated that Bay41-4109 had relatively good drug metabolism parameters (Deres K., Schroder C. H., Paessens A., et al. Science, 2003, 299 (5608):893-896). A study on its mechanism of action showed that HAP changed the angle between dimers forming nucleocapsid, resulting in the formation of unstable swelled nucleocapsid, and accelerating the degradation of core protein by interacting with 113-143 amino acid residues of core protein (Hacker H. J., Deres K., Mildenberger M., et al., Biochem. Pharmacol. 2003, 66(12):2273-2279). WO99/54326 and WO99/54329 disclosed 2-pyridyl substituted and 2-thiazolyl substituted dihydropyrimidine compounds, respectively.